SALICYLANILIDES AND SUBSTITUTED PHENOLS

Question 1

SUBSTANCES

Answer 1

Salicylanilides (SA):
Brotianide, Clioxanide, Closantel (AN), Niclosamide (AC), Oxyclozanide, Rafoxanide

Substituted phenols (SP):
Bithionol, Disophenol (AN), Dichlorophene (AC) Hexachlorophene, Niclofolan, Menichlofolan, Nitroxinil and  Diamphenethide (is an aromatic amide)                                                                    Nitroscanate (AC, AN) (only in dogs)

Question 2

MECHANISM OF ACTION

Answer 2

Uncoupling of oxidative phosphorylation processes. These compounds act as protonophores, allowing hydrogen ions to leak through the inner mitochondrial membrane

Question 3

ANTHELMINTIC SPECTRUM

Answer 3

• They are used in Ov and Bo extensively against fasciolosis and some agent against haemonchosis* (hematophagous nematodes, e.g. Haemonchus* and Bunostomum).
• Lowered efficacy of a number of the salicylanilides and substituted phenols against immature flukes may be due to the high protein binding of these drugs in the blood. A number of these compounds, appear to have activity against 6-wkold flukes in Bo + Ov
• Diamphenetide is unique - high activity against the youngest immature stages, a diminution of activity as the flukes mature
• They are generally ineffective against nematodes (due to a lack of drug uptake).
• Some antinematodal activity: e.g. Closantel, Disophenol, Nitroscanate
• Nitroscanate, Dichlorophen & Nicliosamide are active against tapeworms (Tenia spp., the first 2 drugs against Dipylidium, little or variable efficacy against Echinococcus spp.)

Question 4

PHARMACOKINETIC FEATURES

Answer 4

• The fasciolicidal effects of salicylanilides (such as Closantel) in Ov depend on persistence of the drug in plasma, which influences their transport throughout the body and rate of elimination.
• Closantel, Rafoxanide, and Oxyclozanide have long terminal half-lives in sheep (14.5, 16.6, and 6.4 days, respectively), which are related to the high plasmaprotein binding (>99%) of these 3 drugs.
• Secretion via the liver + bile is important for drugs active against adult Fasciola spp., concentrations of fasciolocides + their metabolites are higher in faeces than in urine.
• Residues in liver are detectable for weeks after administration. /persistence, however, is the need for longer withholding periods/.
• Oxyclozanide also is bound to plasma protein and then metabolized in the liver to the anthelmintically active glucuronide + excreted in high concentration in the bile duct, where it encounters the mature flukes.
• Diamphenetide is metabolized in the gut, and to a greater extent in the liver=> active metabolite that can enter hepatic cells & exert its antiparasitic effect against very young stages of the fluke. (practically a pro-drug)
• Because rumen bacteria metabolize and destroy the activity of Nitroxinil, it must be injected.

Question 5

Why mature flukes are more vulnerable to most fasciolicides?

Answer 5

• Immature flukes in the liver parenchyma ingest mainly liver cells, which contain little anthelmintic; plasma-protein binding limits entry of the drug into the tissue cells.
• As the flukes grow/migrate through the liver, they cause extensive haemorrhaging & come into contact with anthelmintic bound to plasma protein.
• When they reach the bile ducts, they are in the main excretory channels for the active metabolites of the fasciolicides and are exposed to toxic concentrations.

Question 6

SIDE-EFFECTS - TOXICITY

Answer 6

• General uncouplers of oxidative phosphorylation, their TI are lower (4-8) many other anthelmintic agent.
• Mild anorexia & unformed faeces may be seen after treatment at recommended doses.
• High dosages may cause blindness, hyperthermia, convulsions, and death — classic signs of uncoupled phosphorylation.
• Adverse effects are most commonly seen in animals that are severely stressed, in poor condition nutritionally or metabolically (cachexia), or that have severe parasitic infections.

Question 7

APPLICATION

Answer 7

Are all given PO, except Nitroxinil, which is normally given SC